Prenatal Sevoflurane Exposure Impairs the Learning and Memory of Rat Offspring via HMGB1-Induced NLRP3/ASC Inflammasome Activation.

Abstract

The neurotoxic effects of sevoflurane anesthesia on the immature nervous system have aroused public concern, but the specific effects and mechanism remain poorly understood. Pyroptosis caused by the activation of the NLRP3 inflammasome is pivotal for cell survival and acts as a key player in cognitive impairment. This study was carried out to determine the critical role of the NLRP3 inflammasome and high-mobility group box 1 (HMGB1) in sevoflurane-induced cognitive impairment. On gestational day 20 (G20), 3% sevoflurane was administered for 4 h to pregnant rats. The hippocampus and cerebral cortex of the offspring were harvested at postnatal day 1 (P1) for Western blotting and immunofluorescence staining. Pregnant rat sevoflurane exposure increased the protein levels of NLRP3, ASC, cleaved-caspase 1 (p20), mature-IL-1β (m-IL-1β), and HMGB1 in the cerebral cortex and hippocampus of offspring rats. More microglial cells of offspring were also observed after sevoflurane anesthesia. The Morris water maze (MWM) test was implemented to evaluate cognitive function from postnatal day 30 (P30) to postnatal 35 (P35) of offspring. The sevoflurane-treated offspring took longer than the control rats to find the MWM platform during the learning phase. Furthermore, they had a longer travel distance and less time in the target quadrant than the control rats in the probe trial. Maternal intraperitoneal injection of glycyrrhizin (an inhibitor of HMGB1) attenuated the sevoflurane-induced microglia and NLRP3/ASC inflammasome activation and cognitive impairment of offspring. Simultaneously, the sevoflurane-induced increase in Toll-like receptors (TLR4) and nuclear factor-κB (NF-κB) was significantly reduced by glycyrrhizin. We concluded that the HMGB1 inhibitor may repress the sevoflurane-induced activation of the NLRP3/ASC inflammasome and cognitive dysfunction and that TLR4/NF-κB signaling maybe the key pathway, at least in part.